Apatinib | Kinase Inhibitor | VEGFR-2 Inhibitor | KDR Inhibitor | Angiogenesis Inhibitor | Anti-Tumor Drug

Apatinib [N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide] is an orally available, selective small molecule inhibitor of vascular endothelial growth factor-2 (VEGFR-2 also known as KDR) tyrosine kinase. It is more potent than Sunitinib in inhibiting VEGFR2 (IC₅₀ Apatinib, Sunitinib = 0.001, 0.005 uM) [1, 2].

Apatinib is an analogue of Valatinib and shows similar anti-angiogenic/anti-tumour efficacy. It binds with VEGFR-2 tyrosine kinase targeting the intracellular ATP binding site of the receptor, preventing phosphorylation and subsequent downstream signalling. Apatinib has shown a superior in vivo efficacy compared to Valatinib in xenograft models.

Apatinib has been approved by the Chinese Food and Drug Administration (CFDA) in October 2014 for the treatment of metastatic gastric carcinoma. It is an investigational cancer drug in many other countries including USA, EU etc and currently undergoing clinical trials as a potential targeted treatment for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.

Apatinib: 2D and 3D Structure

Angiogenesis, Tumor Angiogenesis and VEGFRs

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types.

Tumor angiogenesis plays a critical role in the malignant tumor growth and metastasis. When tumors grow beyond 1 mm³, angiogenesis or generation of vascular arborizations by budding from existing vessels is necessary to provide enough blood for the survival of tumor cells. The growth speed and tendency of metastasis of tumors are associated with the level of neovascularization factors and the quantity of nascent microvessels. Since the hypothesis “anti-angiogenesis therapy” was put forward by Folkman in early 1970s, people have made considerable progress in this field, and inhibiting angiogenesis of tumors has been universally accepted as a new anticancer strategy. 

Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play significantly important roles in angiogenesis of tumors, and they are both important targets in blocking angiogenesis of tumors. Vascular endothelial growth factor (VEGF) is the foremost factor in vivo promoting the angiogenesis. The binding of VEGF with vascular endothelial growth factor receptor (VEGFR) in endothelial cells leads to various reactions of angiogenesis, such as cells proliferation, cells metastasis, the increase of vascular permeability, and the move of endothelial cells precursors out of marrow. VEGFR family comprises VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1) and VEGFR3 (Flt-4). Promotion of the angiogenesis is mainly mediated by the bonded VEGF and VEGFR2 (KDR/Flk-1).

Compared with traditional cytotoxic drugs which inhibit the growth of tumors, angiogenesis targeting drugs are more specific and less toxic as well as helpful to overcome the drug resistance of tumors and can be used for the treatment of various tumors [3, 4].

Apatinib as Kinase Inhibitor

In vitro enzyme experiments showed that Apatinib was an even more selective inhibitor of VEGFR-2 than Sunitinib, with an IC₅₀ of 0.001 uM and 0.005 uM, respectively. Apatinib could also potently suppress the activities of Ret, c-Kit and c-Src with an IC₅₀ of 0.013 uM, 0.429 uM and 0.53 uM, respectively. Apatinib had no significant effects on EGFR, Her-2 or FGFR1 in concentrations up to 10 uM [1].

Summary

Common name: YN968D1; YN 968D1; YN-968D1

Trademarks: -

Molecular Formula: C24H23N5O

CAS Registry Number: 811803-05-1; 1218779-75-9 (mesylate)

CAS Name: N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide

Molecular Weight: 397.48

SMILES:O=C(NC1=CC=C(C2(C#N)CCCC2)C=C1)C3=CC=CN=C3NCC4=CC=NC=C4

InChI Key: WPEWQEMJFLWMLV-UHFFFAOYSA-N

InChI: InChI=1S/C24H23N5O/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30)

Mechanism of Action: Kinase Inhibitor; KDR Inhibitor; Multi-Kinase Inhibitor

Activity: Treatment of Metastatic Gastric Carcinoma; Anti-cancer Agents; Angiogenesis Inhibitors

Status: Launched 2014 (China)

Chemical Class: Small-molecules; Nitrile containing; Pyrimidine containing

Originator: Advenchen Laboratories (USA)/ Jiangsu Hengrui Medicine Co. Ltd (China)

Apatinib Synthesis

US20040259916A1: It appears to be the industrial process.

Identification:

1H NMR (Estimated) for Apatinib

References:
1. Tian, S.; et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011, 102(7), 1374-80. (FMO only)
2. Chen, G. Six membered amino-amide derivatives an angiogenisis inhibitors. US20040259916A1
3. Yuan, K.; et al. The salts of n-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridyl methyl)amino-3-pyridinecarboxamide. WO2010031266A1
4. Sharma, P. S.; et al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets 2011, 11(5), 624-53. (FMO only)

Drugs in Clinical Pipeline: Foretinib | EXEL-2880 | HGF, VEGF Inhibitor | Multi-Kinase Inhibitor | Angiogenesis Inhibitor

Foretinib [N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide] is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of Foretinib to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft [1].

Foretinib: 2D and 3D Structure

Foretinib inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and inhibits growth of tumor cells under both normoxic and hypoxic conditions with increased potency against Met-amplified gastric cancer cell lines. In vitro, Foretinib inhibits HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells that are thought to contribute to invasion, metastasis, and angiogenesis in vivo. Consistent with this profile, Foretinib inhibits tumor formation in an in vivo murine model of lung metastasis. Foretinib therefore has the potential to prevent tumor growth through a direct effect on tumor cell proliferation and indirectly through inhibition of the host angiogenic response.

Using high-throughput unbiased screening approach to identify small-molecule kinase inhibitors with potent activity against orphan RTK c-ros oncogene 1 (ROS1), researchers found that Foretinib is a highly effective inhibitor of ROS1 in human and murine model systems, demonstrating greater potency compared with Crizotinib both in vitro and in vivo. Despite the reported binding affinity (K_d) of Crizotinib for ROS1 being lower than that of Foretinib (4.4 nM and 14 nM, respectively), researchers found Foretinib to be a significantly more potent ROS1 inhibitor in cell-based assays, accentuating that the in vitro binding affinity does not directly translate to inhibitory efficacy in the cellular context.

Exelixis is credited with discovering Foretinib. It was called EXEL-2880 at Exelixis. Subsequently, the compound was licensed to GlaxoSmithKline in December 2007 where it was called GSK1363089. It is in Phase II trials for various cancers.

The activity of Foretinib is as follows:

IC₅₀ (Met enzyme assay) = 0.4 ± 0.04 nM

IC₅₀ (Ron enzyme assay) = 3 ± 0.2 nM

IC₅₀ (KDR enzyme assay) = 0.86 ± 0.04 nM

IC₅₀ (Flt-1 enzyme assay) = 6.8 ± 0.7 nM

IC₅₀ (Flt-4 enzyme assay) = 2.8 ± 0.4 nM

IC₅₀ (KIT enzyme assay) = 6.7 ± 0.6 nM

IC₅₀ (Flt-3 enzyme assay) = 3.6 ± 0.4 nM

IC₅₀ (PDGFR-α enzyme assay) = 3.6 ± 0.4 nM

IC₅₀ (PDGFR-β enzyme assay) = 9.6 ± 1.1 nM

IC₅₀ (Tie-2 enzyme assay) = 1.1 ± 0.1 nM

IC₅₀ (FGFR1 enzyme assay) = 660 ± 50 nM

IC₅₀ (EGFR enzyme assay) = 2990 ± 38 nM


Common Name: Foretinib

Synonyms: XL880; XL 880; XL-880; EXEL-2880; GSK1363089; GSK 1363089; GSK-1363089; SK1363089; GSK089

IUPAC Name: N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

CAS Number: 849217-64-7

SMILES: 

Mechanism of Action: Kinase Inhibitor; Multi-Kinase Inhibitor; MET Kinase Inhibitor; KDR Inhibitor

Indication: Various Cancers; Anti-tumor Agents; Angiogenesis Inhibitor

Development Stage: Phase II

Company: Exelixis Inc/GlaxoSmithKline

1H NMR (Estimated) for Foretinib

References:
1. Qian, F.; et. al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69(20), 8009-8016.

Drugs in Clinical Pipeline: AZD2932

AZD2932 [2-(4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)acetamide] is a potent and mutil-targeted protein tyrosine kinase inhibitor with IC₅₀ of 8 nM, 4 nM, 7 nM, and 9 nM for VEGFR-2, PDGFR-β, Flt-3, and c-Kit, respectively [1].

AZD2932 does not inhibit the various cytochrome P450 isoforms with the worst IC₅₀ being against 2C9 (IC₅₀ = 8.0 uM). It has a good fraction unbound between 3.3% free in human and 7.0% in dog sera and has no activity against hERG (IC₅₀ = 137 uM).

AZD2932 belong to the quinazoline family of kinase inhibitors, where fine-tuning of the lipophilicity of the pyrazole series provided a balanced 1:1 ratio of activity vs both VEGFR-2 and PDGFR-β. Moreover, AZD2932 potently inhibited both PDGFR-α (IC₅₀ = 2 nM) and PDGFR-β (IC₅₀ = 4 nM) phosphorylation with a correlation close to 1:1.

Common Name: AZD2932

Synonyms: AZD2932; AZD 2932; AZD-2932

IUPAC Name: 2-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)acetamide

CAS Number: 883986-34-3

SMILES:COC1=CC2=C(C(OC3=CC=C(CC(NC4=CN(C(C)C)N=C4)=O)C=C3)=NC=N2)C=C1OC

Mechanism of Action: Kinase Inhibitor; Multi-Kinase Inhibitor; KDR Inhibitor;  PDGFR Inhibitor; Angiogenesis Inhibitor

Indication: Various Cancers; Anti-tumor Therapy

Development Stage: Pre-Clinical

Company: AstraZeneca

References:
1. Ple, P. A.; et. al. Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases. Bioorg Med Chem Lett 2012, 22(1), 262-266.

Drugs in Clinical Pipeline: Vatalanib

Vatalanib [N-(4-chlorophenyl)-4-(pyridine-4-ylmethyl)phthalazin-1-amine] is an orally bioavailable anilinophthalazine compound that has potent antineoplastic activity. Vatalanib binds to and inhibits the protein kinase domain of vascular endothelial growth factor receptors 1 and 2 (VEGFR 1 and VEGFR2); both receptor tyrosine kinases are involved in angiogenesis. This agent also binds to and inhibits related receptor tyrosine kinases, including platelet-derived growth factor (PDGF) receptor, c-Kit, and c-Fms [1]. Preclinical studies demonstrated antitumor activity against a broad range of cancer types, including colorectal, prostate, renal, hepatocellular, myeloma, recurrent glioblastoma multiform and ovarian. The compound has been investigated in phase I/II studies, alone and in combination with chemotherapy.

The activity of Vatalanib is as follows:

IC₅₀ (VEGFR2/KDR, cell-free assay) = 37 nM

IC₅₀ (VEGFR1/FLT1, cell-free assay) = 77 nM

IC₅₀ (VEGFR2/Flk1, cell-free assay) = 270 nM

IC₅₀ (PDGFRB, cell-free assay) = 580 nM

IC₅₀ (VEGFR3/FLT4, cell-free assay) = 660 nM

IC₅₀ (c-Kit, cell-free assay) = 730 nM

IC₅₀ (c-Fms, cell-free assay) = 1400 nM

Common Name: Vatalanib; Vatalanib dihydrochloride

Synonyms:  PTK787; PTK 787; PTK-787; ZK 222584; ZK222584; ZK-222584; CGP 79787; CGP-797870; ZK-232934; CGP79787D; PTK787/ZK 222584; CGP-79787

IUPAC Name: N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine

CAS Number: 212141-54-3; 212141-51-0 (dihydrochloride)

SMILES: C1=CC=C2C(=C1)C(=NN=C2NC3=CC=C(C=C3)Cl)CC4=CC=NC=C4.Cl.Cl

Mechanism of Action: Kinase Inhibitor; VEGFR-2 Inhibitor; KDR Inhibitor

Indication: Metastatic colorectal cancer and NSCLC

Development Stage: Phase II / III trials

Company: Novartis International AG/ Bayer Schering

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulate vasculogenesis (formation of blood vessels occurring by de novo production of endothelial cells) and angiogenesis (formation of new blood vessels from pre-existing vessel). It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. Its normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise and new vessels to bypass blocked vessels. But, when VEGF is overexpressed, it can lead to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply, cancers that can express VEGF are able to grow and metastasize.

Vatalanib (INN, codenamed PTK787 or PTK/ZK) is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib targets all known VEGF receptors (VEGFR1, VEGFR2, VEGFR3), as well as platelet-derived growth factor receptor-beta (PDGFRB) and c-KIT, but is most selective for VEGFR-2. The compound is less potent against VEGFR1/Flt-1, 18-fold against VEGFR3/Flt-4 [1]. It is undergoing clinical trials for metastatic colorectal cancer and NSCLC.

Vatalanib was discovered through high-throughput screening. It has been extensively investigated in Phase I, II and III clinical trials. Encouraging data were obtained from phase II trials examining vatalanib monotherapy administered once or twice daily in previously treated patients with NSCLC [2]. Vatalanib was investigated in the treatment of metastatic colorectal cancer in double-blind, placebo-controlled, phase III studies: Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line (CONFIRM-1 and 2) trials. These trials investigated the effect of 5-FU, leucovorin, and oxaliplatin, (FOLFOX-4) chemotherapy with or without vatalanib as second line therapy of patients with metastatic colorectal cancer. In CONFIRM-1 trials, participants had not yet received any treatment for their cancer; and CONFIRM-2, in which participants had received first-line treatment with irinotecan and fluoropyrimidines. Both trials result showed that the progression-free survival (PFS) time was significantly longer in the vatalanib arm in patients with high levels of lactate dehydrogenase (LDH, an enzyme used as a marker of tissue breakdown) [3, 4]. However, interim results from phase III trials of vatalanib in combination with FOLFOX 4 chemotherapy as a second-line treatment in CONFIRM-2 trials, suggested no significant benefit in overall survival (OS). Thus, multitargeted TKIs are yet to show survival benefit in phase II trials when combined with chemotherapeutics.

The possible reasons for why vatalanib treatment did not show a clear benefit with FOLFOX 4 regimen in metastatic colorectal cancer patients could be the simple explanation that it is not as effective an agent at administered doses, vatalanib has a considerably shorter half-life (approx. 6 h), and the phase III trials for vatalanib used a single daily dose of the drug. Contradicting these data, however, is the fact that pharmacokinetic data suggest that an active dose of vatalanib is maintained in the blood circulation for 24 h, and that it has a rapid and pronounced anti-vascular effect [5]. Another explanation could be the off-target effects (i.e. other than on the VEGF receptor kinases). For example, vatalanib might target PDGFR-beta on perivascular cells. This action was shown in mice to be beneficial for vascular targeting, since the PDGF-B-PDGFR-beta axis is known to control vascular stabilization/maturation by recruitment of supporting perivascular cells. Blocking PDGFR-beta, however, may interfere with vascular normalization, by blocking perivascular cell recruitment and excessive vessel pruning, and thus prevent the synergistic effect of combined therapy [6]. Thus, the clinical benefit of targeting perivascular cells in addition to endothelial cells with multi-targeted TKIs in the context of chemotherapy still remains unclear.

The adverse effects of vatalanib appear similar to those of other VEGF inhibitors. The most common side effects associated with vatalanib were observed to be high blood pressure, gastrointestinal upset (diarrhea, nausea, and vomiting), fatigue, and dizziness [7, 8].

References:

1. Wood, J. M.; et. al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000, 60(8), 2178-2189.

2.    Scagliotti, G.; Govindan, R. Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Oncologist 2010, 15(5), 436-446.

3.    Los, M.; Roodhart, J. M.; Voest, E. E. Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007, 12(4), 443-450.

4.    Scott, E. N.; Meinhardt, G.; et al. Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Expert Opin. Investig. Drugs 2007, 16(3), 367-379.

5.    Morgan, B.; et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 2003, 21(21), 3955-3964.

6.    Jain, R. K. Molecular regulation of vessel maturation. Nat. Med. 2003, 9(6), 685-693.

7.    Mross, K.; et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur. J. Cancer 2005, 41(9), 1291-1299.

8.    Thomas, A. L.; et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J. Clin. Oncol. 2005, 23(18), 4162-4171.

9.    Murakami, M.; Kobayashi, S.; et. al. Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells. Ann. Surg. Oncol. 2011, 18(2), 589-596.